Riley Stephen George, Evans Rachel Anna, Davies Malcolm, Floege Jürgen, Phillips Aled Owain
Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, Wales.
Am J Kidney Dis. 2002 May;39(5):985-1000. doi: 10.1053/ajkd.2002.32772.
Hyperglycemia, although necessary, alone is insufficient for the development of progressive diabetic nephropathy. Two factors implicated in its pathogenesis are mesangial cell activation and/or proliferation and monocyte/macrophage influx. We have shown that prolonged hyperglycemia in the Goto-Kakizaki (GK) rat is associated with renal structural changes similar to those in patients with diabetes before the onset of progressive nephropathy. The aim of the current study is to examine the role of mesangial cell injury and macrophage influx on renal structure and function. After induction of nephritis in either hyperglycemic GK rats or normoglycemic Wistar rats by the administration of Ox-7 antibody, the degree of mesangiolysis and subsequent mesangial proliferation was no different between GK and Wistar rats. Similarly, macrophage influx and mesangial cell activation (assessed by alpha-smooth actin expression) was no different between the two groups. Wistar rats developed marked albuminuria; conversely, no significant proteinuria or albuminuria was seen in GK rats. Analysis of glomerular proteoglycans (PGs) showed an increase in (35)S incorporation into heparan sulfate PGs of GK compared with Wistar rats, with no alteration in glycosaminoglycan chain size or charge density. These changes were kidney specific and not seen in spleen, lung, or heart tissue. Western blot analysis showed increased agrin core protein expression in whole-kidney homogenates of untreated GK rats. Induction of Thy1.1 nephritis was associated with reduced expression of agrin in both GK and Wistar rats. However, agrin expression was greater in GK rats at all times. In summary, acute mesangial cell injury associated with a macrophage influx did not initiate progressive diabetic nephropathy in GK rats. Despite a similar magnitude of glomerular/mesangial injury, GK rats, in contrast to normoglycemic Wistar rats, did not develop proteinuria after the administration of anti-Thy1 antibody. We postulate that altered expression of agrin in this model accounts for the lack of proteinuria and thus may protect against progressive nephropathy.
高血糖虽然是必要条件，但仅靠它本身并不足以导致进行性糖尿病肾病的发生。其发病机制中涉及的两个因素是系膜细胞活化和/或增殖以及单核细胞/巨噬细胞浸润。我们已经表明，Goto-Kakizaki（GK）大鼠长期高血糖与糖尿病患者在进行性肾病发作前出现的肾脏结构变化相似。本研究的目的是探讨系膜细胞损伤和巨噬细胞浸润对肾脏结构和功能的作用。通过给予Ox-7抗体在高血糖的GK大鼠或血糖正常的Wistar大鼠中诱导肾炎后，GK大鼠和Wistar大鼠之间的系膜溶解程度及随后的系膜增殖情况并无差异。同样，两组之间的巨噬细胞浸润和系膜细胞活化（通过α-平滑肌肌动蛋白表达评估）也没有差异。Wistar大鼠出现了明显的蛋白尿；相反，GK大鼠未出现明显蛋白尿或蛋白尿。肾小球蛋白聚糖（PGs）分析显示，与Wistar大鼠相比，GK大鼠硫酸乙酰肝素PGs中（35）S掺入增加，糖胺聚糖链大小或电荷密度无改变。这些变化具有肾脏特异性，在脾脏、肺或心脏组织中未观察到。蛋白质印迹分析显示，未处理的GK大鼠全肾匀浆中聚集蛋白核心蛋白表达增加。Thy1.1肾炎的诱导与GK大鼠和Wistar大鼠中聚集蛋白表达降低有关。然而，GK大鼠在所有时间点的聚集蛋白表达都更高。总之，与巨噬细胞浸润相关的急性系膜细胞损伤并未在GK大鼠中引发进行性糖尿病肾病。尽管肾小球/系膜损伤程度相似，但与血糖正常的Wistar大鼠相比，GK大鼠在给予抗Thy1抗体后并未出现蛋白尿。我们推测，该模型中聚集蛋白表达的改变导致了蛋白尿的缺乏，因此可能对进行性肾病具有保护作用。
